2-pyrrolidinylethyl-2-(7-trifluoromethyl-4-quinolyl-aminobenzoate having analgesic, antipyretic and anti-inflammatory activities

ABSTRACT

2-amino-benzoic acid derivatives, method for making the same as well as its use for therapeutical purposes are proposed. The general formula of 2-amino-benzoic acid derivatives is  &lt;IMAGE&gt;  wherein R represents chlorine or trifluoromethyl, R&#39; is of general formula &lt;IMAGE&gt;   wherein n=0 or 1, m=4, 5, 6, 2-tetrahydropyranyl-methyl, benzyloxymethyl, benzoyloxymethyl of 1(3H)-isobenzofuranone-3-yl. The compounds show an outstanding analgesic and anti-inflammatory activity and a low toxicity.

This is a continuation of application Ser. No. 860,687 filed May 2,1986, now abandoned, which is a continuation of Ser. No. 492,161, filedMay 6, 1983, now abandoned.

BACKGROUND OF THE INVENTION

The present invention relates to 2-amino-benzoic acid derivatives havinggeneral formula (I): ##STR3## wherein R is chlorine or trifluoromethyl;R' is of general formula ##STR4## wherein n=0 or 1 and m=4, 5, 6,2-tetrahydropyranylmethyl, benzyloxymethyl, benzoyloxymethyl and1(3H)-isobenzofuranone-3-yl; and to their non-toxic addition salts.Moreover, the present invention is concerned with a process forproducing 2-amino-benzoic acid derivatives, in particular2-amino-benzoic acid derivatives of the above general formula wherein R'is ##STR5##

The compounds of the above general formula, especially those compoundsin which R' is ##STR6## are pharmacologically active having a remarkableanalgesic and anti-inflammatory activity, and a low toxicity.Accordingly, these compounds, mixed with suitable carriers, can beadministered orally in form of tablets, capsules, syrup, solution, etc.,by injection or rectally wherein a daily dosage ranging from 200 to 1000mg is used.

The compounds show an outstanding analgesic activity, especially uponoral application versus the brewer's yeast test in rat as described byWinter et al. (J. Pharm. Exp. Ther., 150(1), 165-171, 1965). Also thesecompounds have shown anti-inflammatory activity especially upon oralapplication versus the Carrageenin test in rats as described by Winteret al. (Proc. Soc. Exp. Biol. Med., 111, 544-547, 1962). The results forthe analgesic evaluation are expressed as ED₅₀ and those for theanti-inflammatory evaluation expressed as the activity rate observed onadministering the compounds at a dose of 5 mg/kg. All these results arecomparatively shown over acetylsalicylic acid, antrafenine, floctafenineand glafenine in table 1.

                                      TABLE 1                                     __________________________________________________________________________    Compound                          Analgesic activity                                                                     Antiinflammatory                   (as free base)                                                                       R   R'                     ED.sub.50 (mg/kg)                                                                      activity (%)                       __________________________________________________________________________    Example 1                                                                            Cl                                                                                 ##STR7##              38       35,6                               Example 2                                                                            CF.sub.3                                                                           ##STR8##               2,9     38,0                               Example 3                                                                            Cl                                                                                 ##STR9##              67       23,1                               Example 4                                                                            CF.sub.3                                                                           ##STR10##              3,0     23,2                               Example 5                                                                            Cl                                                                                 ##STR11##              5,4     17,3                               Example 6                                                                            CF.sub.3                                                                           ##STR12##              7,0     27,9                               Example 7                                                                            Cl                                                                                 ##STR13##             18,5      5,1                               Example 8                                                                            CF.sub.3                                                                           ##STR14##             14,7     26,2                               Example 9                                                                            Cl                                                                                 ##STR15##             21,7     33,2                               Example 11                                                                           Cl                                                                                 ##STR16##             13,3     21,2                               Example 12                                                                           CF.sub.3                                                                           ##STR17##              6,6     28,8                               Example 14                                                                           Cl                                                                                 ##STR18##             22       19,5                               Example 15                                                                           CF.sub.3                                                                           ##STR19##              9,3     26,1                               Example 16                                                                           Cl  CH.sub.2OCH.sub.2Ph     6,3     27,7                               Example 17                                                                           CF.sub.3                                                                          CH.sub.2OCH.sub.2Ph    64,5     30,5                               Example 18                                                                           Cl  CH.sub.2OCOPh          82,5     31,0                               Example 19                                                                           CF.sub.3                                                                          CH.sub.2OCOPh           3,8     30,5                               Example 20                                                                           Cl                                                                                 ##STR20##             71       26,2                               Example 21                                                                           CF.sub.3                                                                           ##STR21##             26       38,4                               Acetylsalycilic acid              73       23,2                               Antrafenine                       43        3,6                               Floctafenine                       2,2     21,6                               Glafenine                         26,5     25,6                               __________________________________________________________________________

Moreover, the above compounds have shown a low toxicity which makes themuseful in therapy. LD₅₀ for some of the most active compounds arecomparatively shown over glafenine in table 2. Evaluation was madeaccording to the method by Reed-Muench as modified by Pizzi (Human &Biology, 22(3), 151-190, 1950) by oral administration to mice.

                  TABLE 2                                                         ______________________________________                                        Compound                           LD.sub.50                                  (as free base)                                                                         R      R'                 (mg/kg)                                    ______________________________________                                        Example 1                                                                              Cl                                                                                    ##STR22##         2000                                       Example 2                                                                              CF.sub.3                                                                              ##STR23##          630                                       Example 3                                                                              Cl                                                                                    ##STR24##         >2000                                      Example 4                                                                              CF.sub.3                                                                              ##STR25##          635                                       Example 16                                                                             Cl     CH.sub.2OCH.sub.2Ph                                                                              >8000                                      Glafenine                          2100                                       ______________________________________                                    

Compounds of the present invention mixed with pharmaceuticallyacceptable carriers can be administered by oral application in form oftablets, capsules, syrup, solution, etc., by injection and by rectalapplication, at daily doses ranging from 200 to 1000 mg.

The compound (I) of the invention can be made in various ways.

(a) Reaction of a base compound having the general formula (II):##STR26## with a compound having the general formula (III): X--R'.wherein R and R' is as outlined with formula I

R" is C₁ -C₄ -alkyl or hydrogen

X is hydroxy or halogen

In those cases in which compound (II) has ester-like nature, i.e. R" isa C₁ -C₄ alkyl rest, preferable methyl, the reaction is carried out withcompound (III) wherein X is OH; the reaction is properly catalyzed bysodium or sodium hydride and completed at boiling temperature in anaromatic solvent, such as toluene. This reaction is preferably appliedwhen R' is ##STR27## wherein n and m are as defined above, or when R' is2-tetrahydropyranylmethyl.

On the other hand, in those cases in which R" is hydrogen, the reactionis carried out with compound (III) wherein X is a halogen atom, selectedbetween bromine and chlorine. This reaction is preferably applied whenR' is benzyloxymethyl, benzoyloxymethyl and 1(3H)-isobenzofuranone-3-yl.Due to the insolubility of the acids (II, R"=H) in most of organicsolvents, even polar aprotic solvents, as well as their inorganic salts,the use of organic salts, such as triethylamine, tri-n-butylamine or thelike, is preferred which makes solubilization to be attained andconsequently facilitating reaction to a great extent. The reaction thenoccurs under a highly-yielded step by using at room temperaturehexamethylphosphorotriamide or N,N-dimethylformamide as solvent.

Compound (III), wherein X is OH and R' is ##STR28## wherein n is 0 and mis as defined above, are obtained according to the methods described byA. Lespagnol and J. Desprey (Bull. Soc. Chim. France, 3, 606-610, 1961).As for respective analogs with n=1, we have simplified their preparationby modifying the method by H. Najer et al. (Bull. Soc. Chim. France, 3,355-359, 1958), since it has been found out that such intermediates areadvantageously obtained by reacting commercially available2-(2-chloroethoxy)ethanol and the corresponding cyclic amine, thusavoiding under pressure laboratory operations.

(b) Reaction of isatoic anhydride with intermediate alcohols of compound(IV), followed by subsequent alkylation with the corresponding4-chloro-quinoleines (IV), leads to the compounds of general formula (I)in accordance with the following equation: ##STR29##

In the above diagram, R, n and m, for formulas (IV), (V) and (VI), areas defined above in connection with formula (I). The first reaction issuitably conducted in an aromatic solvent, for example, toluene, underthe boiling point of same. The second reaction is suitably conducted inan acid aqueous solution, under the boiling point of same.

These reactions provide an industrially useful process since the isatoicanhydride is evidently a commercially available starting product.

EXAMPLES

A number of examples will now be described in non-limitative manner toillustrate the invention and naturally larger quantities than thoseindicated can be used in industry.

EXAMPLE 1 2-Pyrrolidinylethyl 2-(7-chloro-4-quinolyl)aminobenzoate##STR30##

A mixture containing 18.76 g of methyl2-(7-chloro-4-quinolyl)-aminobenzoate (II, R=Cl, R"=CH₃) (A. Allais etal: "Chim. Ther.", 2, 65-70, 1966) and 10.28 g of1-(2-hydroxyethyl)-pyrrolidine in 150 ml of toluene is heated underoil-bath till distilling about 30 ml of solvent; it is allowed to cooldown to 50° C. and a small scrap of clean sodium is added. Temperatureis gradually increased in order to distill the formed methanol whilesubstituting the toluene which is also removed. Eight hours later andafter having added, at identical intervals, two further scraps ofsodium, the mixture is subjected to reflux for 2 hours; it is observedby thin-layer chromatography (silicagel; eluent, chloroform-methanol9:1) that the transesterification is just complete. The toluene isevaporated under vacuum, the residue is dissolved in 500 ml ofchloroform and then filtered off. The organic extract is washed withwater, 10% sodium hydroxide solution, and water again. After the solventis evaporated, the solid residue weights 22.1 g (yield: 94%). Byrecrystallization in diisopropyl ether, 14.5 g (yield: 62%) ofpale-yellow solid are obtained with m.p. 102°-104° C. and elementalanalysis correct.

IR Spectrum (KBr), cm⁻¹ : 3280, 3000-2740, 1670, 1600, 1570, 1525, 1450,1370, 1245, 1160, 1080, 875, 860, 745.

EXAMPLE 2 2-Pyrrolidinylethyl2-(7-trifluoromethyl-4-quinolyl)aminobenzoate ##STR31##

By treating 19.5 g of methyl2-(7-trifluoromethyl-4-quinolyl)aminobenzoate (II, R=CF₃, R"=CH₃) and9.59 g of 1-(2-hydroxyethyl)pyrrolidine in 145 ml of toluene and in thepresence of sodium as described in Example 1, 19.2 g of a crude materialare isolated. Purification through silicagel, elution with a mixture ofhighly polar chloroform-methanol, and treatment of the product thuspurified with hexane, it yields 11.6 g (56%) of white-yellowish solidwith m.p. 63°-65° C. and elemental analysis C, H, N and F correct.

IR Spectrum (KBr), cm⁻¹ : 3400, 3240, 3000-2740, 1670, 1595, 1580, 1530,1455, 1320, 1250, 1155, 1120, 905, 750.

EXAMPLE 3 2-Piperidinylethyl-2-(7-chloro-4-quinolyl)aminobenzoate##STR32##

By treating 15.54 g of methyl 2-(7-chloro-4-quinolyl)aminobenzoate (II,R=Cl, R"=CH₃), and 10.0 g of 1-(2-hydroxyethyl)piperidine in 100 ml oftoluene and in the presence of sodium as described in Example 1, 17.0 gof a crude material are isolated. By recrystallization in diisopropylether and active carbon, 12.8 g (yield: 63%) of pale-yellow solid areobtained with m.p. 100°-101° C. and elemental analysis correct.

IR Spectrum (KBr), cm⁻¹ : 3300, 3030, 2920, 2900-2760, 1680, 1600, 1575,1520, 1450, 1250, 1160, 1065, 865, 740.

EXAMPLE 4 2-Piperidinylethyl2-(7-trifluoromethyl-4-quinolyl)aminobenzoate ##STR33##

By treating 17.31 g of methyl2-(7-trifluoromethyl-4-quinolyl)aminobenzoate (II, R=CF₃, R"=CH₃) and9.56 g of 1-(2-hydroxyethyl)-piperidine in 130 ml of toluene and in thepresence of sodium as described in Example 1, 17.9 g of a crude materialare isolated. Purification through silicagel and recrystallization indiisopropyl ether enables to isolate 13.3 g (yield: 60%) of white solidwith m.p. 78°-80° C. and elemental analysis C, H, N, F correct.

IR Spectrum (KBr), cm⁻¹ : 3440, 3320, 3000-2700, 1695, 1605, 1580, 1530,1380, 1325, 1255, 1150, 1130, 825, 740.

EXAMPLE 5 2-Homopiperidinylethyl 2-(7-chloro-4-quinolyl)aminobenzoate##STR34##

By treating 18.76 of methyl 2-(7-chloro-4-quinolyl)aminobenzoate (II,R=Cl, R"=CH₃) and 12.72 of 1-(2-hydroxyethyl)homopiperidine in 150 ml oftoluene and in the presence of sodium as described in Example 1, 22.07 gof a crude material are isolated. By recrystallization in diisopropylether, 15.5 g (yield: 61%) of a yellowish solid are obtained with m.p.76.5-78° C. and elemental analysis C, H, N, Cl correct.

IR Spectrum (KBr), cm⁻¹ : 3280, 3000-2760, 1675, 1605, 1570, 1520, 1450,1320, 1240, 1160, 1080, 875, 745.

EXAMPLE 6 2-Homopiperidinylethyl2-(7-trifluoromethyl-4-quinolyl)aminobenzoate ##STR35##

By treating 17.31 g of methyl2-(7-trifluoromethyl-4-quinolyl)aminobenzoate (II, R=CF₃, R"=CH₃), 10.5g of 1-(2-hydroxyethyl)homopiperidine in 130 ml of toluene and in thepresence of sodium as described in Example 1, 20.6 g of a crude materialare isolated. The recrystallization in diisopropyl ether enables toisolate 13.7 g (yield: 60%) of a whitish solid with m.p. 72°-75° C. andelemental analysis C, H, N, F correct.

IR spectrum (KBr), cm⁻¹ : 3420, 3000-2790, 1680, 1605, 1580, 1530, 1450,1380, 1320, 1250, 1155, 1025, 900, 745.

EXAMPLE 7 2-(2-Pyrrolidineethoxy)ethyl2-(7-chloro-4-quinolyl)aminobenzoate ##STR36##

By treating 18.76 g of methyl 2-(7-chloro-4-quinolyl)aminobenzoate (II,R=Cl, R"=CH₃) and 14.14 g of 2-(2-pyrrolidineethoxy)ethanol in 150 ml oftoluene and in the presence of sodium as described in Example 1, 16.2 gof a crude material are isolated. Purification through silicagel andcrystallization in hexane enables to isolate 10.81 g (yield: 41%) of ayellow solid with m.p. 60°-63° C. and elemental analsysis C, H, N, Clcorrect.

IR Spectrum (KBr), cm⁻¹ : 3290, 3000-2890, 1670, 1610, 1575, 1525, 1455,1250, 1085, 860, 745.

EXAMPLE 8 2-(2-Pyrrolidineethoxy)ethyl2-(7-trifluoromethyl-4-quinolyl)aminobenzoate ##STR37##

By treating 17.31 g of methyl2-(7-trifluoromethyl-4-quinolyl)aminobenzoate (II, R=CF₃, R"=CH₃), and11.78 g of 2-(2-pyrrolidineethoxy)ethanol in 150 ml of toluene and inthe presence of sodium as described in Example 1, 13.9 g of a crudematerial are isolated under nitrogen atmosphere. Purification throughsilicagel and crystallization in hexane enables to isolate 6.95 g(yield: 30%) of a white solid with m.p. 58°-61° C. and elementalanalysis C, H, N, F correct.

IR Spectrum (KBr), cm⁻¹ : 3400, 3240, 3000-2780, 1675, 1595, 1585, 1530,1455, 1380, 1325, 1250, 1160, 1115, 750.

EXAMPLE 9 2-(2-Pyrrolidineethoxy)ethyl2-(7-chloro-4-quinolyl)-aminobenzoate ##STR38##

By treating 18.76 g of methyl 2-(7-chloro-4-quinolyl)aminobenzoate (II,R=Cl, R"=CH₃), and 15.38 g of 2-(2-piperidineethoxy)ethanol in 150 ml oftoluene and in the presence of sodium as described in Example 1, 20.32 gof a resinuous crude material are isolated. Subsequent treatment with 50ml of hexane and decantation results in a solid material which isrecrystallized from diisopropyl ether. 12.2 g (yield: 45%) of ayellowish solid are obtained with m.p. 75°-79° C. and elemental analysisC, H, N, Cl correct.

IR Spectrum (KBr), cm⁻¹ : 3440, 3240, 3000-2660, 1675, 1600, 1580, 1530,1450, 1375, 1255, 1130, 1085, 950, 745.

EXAMPLE 10 2-(2-Piperidineethoxy)ethyl2-(7-trifluoromethyl-4-quinolyl)aminobenzoate ##STR39##

By treating 17.31 g of methyl2-(7-trifluoromethyl-4-quinolyl)aminobenzoate (II, R=CF₃, R"=CH₃), and15.4 g of 2-(2-piperidineethoxy)ethanol in 150 ml of toluene and in thepresence of sodium as described in Example 1, 22.1 g of a crude materialare isolated. Subsequent treatment with hexane (50 ml) andrecrystallization of the insolute in diisopropyl ether, 10.4 g (yield:43%) of a yellowish solid are obtained with m.p. 81°-83° C. andelemental analysis C, H, N, F correct.

IR Spectrum (KBr), cm⁻¹ : 3290, 3000-2700, 1675, 1610, 1580, 1530, 1455,1250, 1150, 745.

EXAMPLE 11 2-(2-Homopiperidineethoxy)ethyl2-(7-chloro-4-quinolyl)aminobenzoate ##STR40##

By treating 18.76 g of methyl 2-(7-chloro-4-quinolyl) aminobenzoate (II,R=Cl, R"=CH₃) and 16.63 g of 2-(2-homopiperidineethoxy)ethanol in 150 mlof toluene and in the presence of sodium, as described in Example 1,29.3 g of a resinous crude material are isolated. Subsequent treatmentin 50 ml of hexane and decantation results in a solid material which isconsecutively recrystallized in hexane and diisopropyl ether. 13.3 g(yield: 49%) of a yellowish solid are obtained with m.p. 62°-64° C. andelemental analysis C, H, N, Cl correct.

IR Spectrum (KBr), cm⁻¹ : 3240, 3000-2700, 1675, 1600, 1570, 1520, 1445,1245, 1080, 875, 740.

EXAMPLE 12 2-(2-Homopiperidineethoxy)ethyl2-(7-trifluoromethyl-4-quinolyl)aminobenzoate ##STR41##

By treating 17.31 g of methyl2-(7-trifluoromethyl-4-quinolyl)aminobenzoate (II, R=CF₃, R"=CH₃), 13.85g of 2-(2-homopiperidineethoxy)ethanol, 150 ml of toluene and in thepresence of sodium, as described in Example 1, 20.3 g of a resinouscrude material are isolated. Subsequent crystallization in n-pentane anddiisopropyl ether yields 12.1 g (47.5%) of a white-yellowish solid withm.p. 53.56° C. and elemental analysis C, H, N, F correct.

IR Spectrum (KBr), cm⁻¹ : 3260, 3000-2700, 1670, 1595, 1580, 1520, 1445,1375, 1315, 1240, 1155, 1105, 740.

EXAMPLE 13

(a) 2-(2-Homopiperidineethoxy)ethanol

A mixture, under stirring, containing 59.81 g of hexamethylenimine and50.66 g of sodium bicarbonate in 1 liter of absolute ethanol, is allowedto drip 56.06 g of 2-(2-chloroethoxy)ethanol, and then subjected toreflux for 24 hours. It is cooled, the insoluble is filtered off, theethanol is distilled under vacuum and the residue (82.1 g) is dissolvedin ethyl ether, filtered again and, under cooling, 55 ml ofhydrochloride acid (g) 10N ethanolic solution are added. After 30minutes the precipitated hydrochloride is filtered and dried, thusobtaining 80 g (yield: 70%) of a white solid, m.p. 96°-99° C. andanalysis correct.

The hydrochloride thus obtained in 225 ml of water is brought to highlybasic pH by addition of concentrated NH₄ OH; it is extracted withmethylene chloride, dried and solvent is evaporated. By distillationunder vacuum of the residue, 68.5 g (yield: 61%) of a colorless liquidare obtained with b.p. 125° C./2.5 torr, n_(D) ²⁰ =1.4819.

IR Spectrum (film), cm⁻¹ : 3400, 3000-2600, 1450, 1350, 1320, 1130,1060, 890.

By operating as described in (a) for 2-(2-pyrrolidine ethoxy)ethanol and2-(2-(2-piperidineethoxy)ethanol, both compounds are obtained with thefollowing features:

(b) 2-(2-pyrrolidineethoxy)ethanol: n_(D) ²⁰ =1.4695; m.p. (HCl),104°-108° C. IR Spectrum (film), cm⁻¹ : 3400, 3000-2700, 1460, 1350,1125, 1060, 880.

(c) 2-(2-piperidineethoxy)ethanol: n_(D) ²⁰ =1.4765; m.p. (HCl),114°-118° C. IR Spectrum (film), cm⁻¹ : 3500, 3000-2600, 1440, 1340,1300, 1260, 1130, 1050, 1030, 850, 750.

EXAMPLE 14 2-Tetrahydropyranylmethyl2-(7-chloro-4-quinolyl)aminobenzoate ##STR42##

By treating 15.4 g of methyl 2-(7-chloro-4-quinolyl)aminobenzoate (II,R=Cl, R"=CH₃), 8.46 g of 2-hydroxymethyltetrahydropyran, 125 ml oftoluene and in the presence of sodium, as described in Example 1, 19.8 gof a crude material are isolated. This material is dissolved in 250 mlof diisopropyl ether and 7 ml of hydrochloric acid (g) 10N ethanolicsolution are added under cooling in water-ice bath. After 15 minutes theprecipitated hydrochloride is filtered off, dried (19.45 g; 91%) andrecrystallized in acetonitrile. 14.34 g (yield: 67%) of thehydrochloride--yellow solid--are obtained with m.p. 187°-187.5° C. andelemental analysis C, H, N, Cl correct.

The above hydrochloride, dissolved in 300 ml of warm water, is broughtto highly basic pH with concentrated NH₄ OH solution. The resinous solidthus obtained is ground with diisopropyl ether and filtered off. Afterdrying, a white solid weighing 11.8 g (yield: 60%) is obtained with m.p.93°-94° C. and elemental analysis C, H, N, Cl correct.

IR Spectrum (Kbr), cm⁻¹ : 3260, 3000-2800, 1680, 1605, 1570, 1520, 1445,1250, 1080, 745.

EXAMPLE 15 2-Tetrahydropyranylmethyl2-(7-trifluoromethyl-4-quinolyl)aminobenzoate ##STR43##

By treating 16.97 g of methyl 2-(7-trifluoromethyl-4-quinolylaminobenzoate (II, R=CF₃, R"=CH₃), 8.42 g of2-hydroxymethyltetrahydropyran, 125 ml of toluene, and in the presenceof sodium, as described in Example 1, 18.73 g of a crude material areisolated. The hydrochloride is formed as described in the above exampleand recrystallized in acetonitrile, thus obtaining 13.1 g (yield: 62%)of a yellow solid, m.p. 217°-221° C. and elemental analysis C, H, N, Clcorrect. The base obtained by neutralization is dried and ground withhexane. Yield: 10.97 g (52%) of a white solid with m.p. 76°-80° C. andelemental analysis C, H, N, F correct.

IR Spectrum (KBr), cm⁻¹ : 3260, 2940, 2850, 1690, 1610, 1580, 1530,1455, 1325, 1250, 1150, 1130, 750.

EXAMPLE 16 Benzyloxymethyl 2-(7-chloro-4-quinolyl)aminobenzoate (I,R=Cl, R"=--CH₂ --O--CH₂ --Ph)

To a suspension of 14.94 g of 2-(7-chloro-4-quinolyl)aminobenzoic acid(II, R=Cl, R"=H) in 300 ml of hexamethylphosphorotriamide, 6.32 g of drytriethylamine are added and the mixture is stirred till the whole acidturns into solution. Then 9.79 g of benzylchloromethyl ether are addedby stirring for 48 hours at room temperature. The mixture is poured onto1.5 liters of water, then allowed to stand for a few hours, filtered andrepeatedly washed with water. After drying (20.5 g), it isrecrystallized from a acetonitrile thus obtaining 18.4 g (yield: 88%) ofa whitish solid, m.p. 131°-134° C. and elemental analysis C, H, N, Clcorrect.

IR Spectrum (KBr), cm⁻¹ : 3300, 3020, 2950, 1690, 1610, 1565, 1445,1250, 1150, 1040, 940, 735.

EXAMPLE 17 Benzyloxymethyl 2-(7-trifluoromethyl-4-quinolyl)aminobenzoate(I, R=CF₃, R'=--CH₂ --O--CH₂ --Ph)

By treating 10.3 g of 2-(7-trifluoromethyl-4-quinolyl)aminobenzoic acid(II, R=CF₃, R"=H) in 200 ml of hexamethylphosphorotriamide, 3.93 g oftriethylamine and 6.08 g of benzylchloromethyl ether as described inExample 16, 17.22 g of a crude material are isolated which byrecrystallization in acetonitrile yields 10.12 g (72%) of a whitishsolid, m.p. 87.5°-89° C. and elemental analysis C, H, N, F correct.

IR Spectrum (KBr), cm⁻¹ : 3260, 3060-2090, 1685, 1605, 1570, 1530, 1320,1245, 1150, 1040, 920, 740.

EXAMPLE 18 Benzoyloxymethyl 2-(7-chloro-4-quinolyl)aminobenzoate (I,R=Cl, R'=--CH₂ --O--CO--Ph)

By treating 11.05 g of 2-(7-chloro-4-quinolyl)aminobenzoic acid (II,R=Cl, R"=H) in 225 ml of hexamethylphosphorotriamide, 4.70 g oftriethylamine and 7.90 g of chloromethyl benzoate as described inExample 16, 12.6 g (yield: 70%) are isolated after recrystallization inacetonitrile as a yellowish solid; m.p. 139°-141° C. and elementalanalysis C, H, N, Cl correct.

IR Spectrum (KBr), cm⁻¹ : 3320, 3040-2980, 1740, 1685, 1580, 1520, 1450,1240, 1150, 1045, 1025, 740, 710.

EXAMPLE 19 Benzoyloxymethyl2-(7-trifluoromethyl-4-quinolyl)aminobenzoate (I, R=CF₃, R'=--CH₂--O--CO--Ph)

By treating 10.9 g of 2-(7-trifluoromethyl-4-quinolyl)aminobenzoic acid(II, R=CF₃, R"=H) in 200 ml of hexamethylphosphorotriamide, 4.15 g oftriethylamine and 7.0 g of chloromethyl benzoate as described in Example16, 8.4 g (yield: 56%) are isolated after recrystallization inacetonitrile; m.p. 100°-103° C. and elemental analysis C, H, N, Fcorrect.

IR Spectrum (KBr), cm⁻¹ : 3300, 3040-2980, 1735, 1690, 1580, 1530, 1450,1325, 1240, 1145, 1040, 975, 745, 710.

EXAMPLE 20 1(3H)-isobenzofuranone-3-yl2-(7-chloro-4-quinolyl)aminobenzoate ##STR44##

By treating 9.82 g of 2-(7-chloro-4-quinolyl)aminobenzoic acid (II,R=Cl, R"=H) in 200 ml of hexamethylphosphorotriamide, 4.16 g oftriethylamine and 8.75 g of 3-bromo-1(3H)-isobenzofuranone as describedin Example 16, 15 g are isolated which recrystallization in acetonitrileyields 11.9 g (84%) of a yellow solid, m.p. 213°-215° C. and elementalanalysis of C, H, N, Cl correct.

IR Spectrum (KBr), cm⁻¹ : 3300, 3040, 1780, 1695, 1610, 1585, 1525,1455, 1240, 1070, 970, 745.

EXAMPLE 21 1(3H)-isobenzofuranone-3-yl2-(7-trifluoromethyl-4-quinolyl)aminobenzoate ##STR45##

By treating 9.55 g of 2-(7-trifluoromethyl-4-quinolyl)aminobenzoic acid(II, CF₃, R"=H) in 200 ml of hexamethylphosphorotriamide, 3.65 g oftriethylamine and 7.69 g of 3-bromo-1(3H)-isobenzofuranone as describedin Example 16, 11.3 g (yield: 85%) of a yellow solid are isolated afterrecrystallization in acetonitrile, m.p. 218°-220° C. and elementalanalysis of C, H, N, F correct.

IR Spectrum (KBr), cm⁻¹ : 3300, 3010, 1780, 1700, 1580, 1540, 1460,1360, 1245, 1155, 1125, 980, 750.

EXAMPLE 22 2-Pyrrolidinylethyl, 2-(7-chloro-4-quinolyl)aminobenzoate##STR46##

(A) 2-Pyrrolidinylethyl antranilate (V, n=0, m=4):

A mixture with 15.07 g of isatoic anhydride and 7.96 g of1-(2-hydroxyethyl)pyrrolidine in 150 ml of toluene is subjected toreflux under stirring for 3 hours. Active carbon is added and thenfiltered off under heating. The toluene is evaporated under reducedpressure, the residue is taken in ethyl ether, the insoluble is filteredoff and the organic solution, under cooling, is extracted twice with 75ml of 6N hydrochloride acid solution. The acid extracts are broughtunder cooling, to basic pH with concentrated ammonium hydroxide solutionand the oil thus separated is extracted with ethyl ether, washed anddried. After the solvent is evaporated, the residue, a yellow oil withn_(D) ²⁰ =1.572 and elemental analysis correct weights 13.8 g (yield:85%). It is distillable in ball furnace with b.p. 185°-190° C./10⁻³-10⁻⁴ Torr.

IR Spectrum (film), cm⁻¹ : 3470, 3360, 3260, 2880, 2800, 1680, 1610,1580, 1480, 1450, 1285, 1235, 1150, 1100, 740.

(B) Reaction with 4,7-dichloroquinoleine (VI, R=Cl):

11.71 g of 2-pyrrolidinylethyl antranilate, as described above, and 9.90g of 4,7-dichloroquinoleine in 50 ml of 2N hydrochloride acid aresubjected to reflux under stirring for 3 hours. The mixture is allowedto cool, the insoluble is filtered off, and the filtrate is brought tostrongly basic pH with saturated sodium carbonate solution. Theseparated solid is filtered off, washed repeatedly and dried. 11.5 g(yield: 58%) are obtained by recrystallization with m.p. 102°-104° C.and elemental analysis correct.

IR Spectrum (KBr), cm⁻¹ : 3280, 3000-2740, 1670, 1600, 1570, 1525, 1450,1370, 1245, 1160, 1080, 875, 860, 745.

EXAMPLE 23 2-Pyrrolidinylethyl2-(7-trifluoromethyl-4-quinolyl)aminobenzoate ##STR47##

A mixture with 96.2 g of 2-pyrrolidinylethyl antranilate and 95.1 g of4-chloro-7-trifluoromethylquinoline in 410 ml of 2N hydrochloride acidis subjected to reflux under stirring for 3 hours. 127 g of a whitishsolid are obtained according to Example 22. Recrystallization inn-pentane yields 95.3 g (54%) of a white-yellowish solid with m.p.65°-68° C. and elemental analysis correct.

IR Spectrum (KBr), cm⁻¹ : 3400, 3240, 3000-2740, 1670, 1595, 1580, 1530,1455, 1320, 1155, 1120, 905, 750.

EXAMPLE 24 2-Piperidinylethyl 2-(7-chloro-4-quinolyl)aminobenzoate##STR48##

(A) 2-Piperidinylethyl antranilate (V, n=0, m=5):

22.95 g of isatoic anhydride are reacted with 13.59 g of1-(2-hydroexyl)piperidine in 220 ml of toluene. 20.53 g (yield: 75%) ofa yellow oil are isolated according to Example 22; n_(D) ²⁰ =1.567 andelemental analysis correct. It may be purified by careful distillationin ball furnace at 175°-190° C./10⁻³, 10⁻⁴ Torr.

IR Spectrum (KBr), cm⁻¹ : 3480, 3370, 2940, 2790, 1690, 1620, 1590,1490, 1455, 1290, 1245, 1160, 1105, 750.

(b) Reaction with 4,7-dichloroquinoleine (VI, R=Cl):

12.41 g of 2-piperidinylethyl antranilate (as described above) and 9.90g of 4,7-dichloroquinoleine in 50 ml of 2N hydrochloride acid aresubjected to reflux for 3 hours. As described in Example 22, and byrecrystallization in diisopropyl ether, 11.4 g (yield: 56%); m.p.101°-102° C. and elemental analysis correct.

IR Spectrum (KBr), cm⁻¹ : 3300, 3030, 2920, 2900-2760, 1680, 1605, 1575,1520, 1450, 1250, 1160, 1065, 865, 740.

EXAMPLE 25 2-Piperidinylethyl2-(7-trifluoromethyl-4-quinolyl)aminobenzoate ##STR49##

By treating 2-piperidinylethyl antranilate (V, n=0, m=5) (51 g) and4-chloro-7-trifluoromethylquinoline (47.6 g) as described in Example 22,and by recrystallization in n-pentane, 51.9 g (yield: 57%) are obtained;m.p. 78°-80° C. and elemental analysis correct.

IR Spectrum (KBr), cm⁻¹ : 3440, 3320, 3000-2760, 1695, 1605, 1580, 1530,1380, 1325, 1255, 1150, 1130, 825, 740.

EXAMPLE 26 2-Homopiperidinylethyl 2-(7-chloro-4-quinolyl)aminobenzoate##STR50##

(A) 2-Homopiperidinylethyl antranilate (V, n=0, m=6):

7.54 g of isatoic anhydride are reacted with 5.36 g of1-(2-hydroxyethyl)-homopiperidine in 100 ml of toluene, 9.46 g of aviscous yellow oil are isolated according to Example 22. By distillationin ball furnace 6.8 g (yield: 70%) of oil are obtained at 180°-195°C./10⁻³, 10⁻⁴ Torr, n_(D) ²⁰ =1.570 and elemental analysis of C, H, Ncorrect.

IR Spectrum (film), cm⁻¹ : 3470, 3360, 1680, 1610, 1580, 1480, 1450,1290, 1240, 1155, 1105, 750, 700.

(B) Reaction with 4,7-dichloroquinoleine (VI, R=Cl):

By treating 2-homopiperidinylethyl antranilate (5.4 g) as abovedescribed and 4,7-dichloroquinoline (4.1 g) according to Example 22, andafter recrystallization, 5.1 g (yield: 55%) are obtained; m.p. 76.5°-78°C. and elemental analysis correct.

IR Spectrum (KBr), cm⁻¹ : 3280, 3000-2760, 1675, 1605, 1570, 1520, 1450,1320, 1240, 1160, 1080, 875, 745.

EXAMPLE 27 2-Homopiperidinylethyl2-(7-trifluoromethyl-4-quinolyl)aminobenzoate ##STR51##

By treating 2-homopiperidinylethyl antranilate (5.40 g) as described inExample 26, and 4-chloro-7-trifluoromethylquinoleine (4.75 g) asdescribed in Example 22, and after recrystallization in diisopropylether, 5.4 g (yield: 58%) are obtained; m.p. 72°-75° C. and elementalanalysis correct.

IR Spectrum (KBr), cm⁻¹ : 3420, 3240, 3000-2790, 1680, 1605, 1580, 1530,1450, 1380, 1320, 1250, 1155, 1025, 900, 745.

EXAMPLE 28 2-(2-Pyrrolidinethoxy)ethyl2-(7-chloro-4-quinolyl)aminobenzoate ##STR52##

(A) 2-(2-Pyrrolidinethoxy)ethyl antranilate (V, n=1, m=4):

11.0 g of 2-(2-pyrrolidinethoxy)ethanol are reacted with 15.07 g ofisatoic anhydride in 170 ml of toluene. 14.5 g (yield: 76%) of a viscousyellow oil are isolated according to Example 22. Then, it is purified bycareful distillation in ball furnace at 175°-190° C./10⁻³, 10⁻⁴ Torr, asa heavy oil of n_(D) ²⁰ =1.5589 and elemental analysis C, H, N, correct.

IR Spectrum (film), cm⁻¹ : 3460, 3380, 3010-2700, 1685, 1615, 1585,1485, 1455, 1290, 1245, 1160, 1100, 860, 750.

(B) Reaction of 4,7-dichloroquinoleine (VI, R=Cl):

By treating 2-(2-pyrrolidinethoxy)ethyl antranilate (7.72 g) asdescribed above, and 4,7-dichloroquinoleine (7.01 g) in 24 ml of 2Nhydrochloride acid and 115 ml of water under reflux for 3 hours,followed by neutralization with sodium bicarbonate, extraction withmethylene chloride and evaporation of solvent, 11.2 g of a material areisolated which after being purified by silicagel solumn chromatographyand crystallization in hexane gives 7.3 g (60%); m.p. 60°-63° C. andelemental analysis correct.

IR Spectrum (KBr), cm⁻¹ : 3290, 3000-2890, 1670, 1610, 1575, 1525, 1455,1250, 1085, 860, 745.

EXAMPLE 29 2-(2-Pyrrolidinethoxy)ethyl2-(7-trifluoromethyl-4-quinolyl)aminobenzoate ##STR53##

By treating 2-(2-pyrrolidinethoxy)ethyl (7.7 g) as described in Example28, and 4-chloro-7-trifluoromethylquinoleine (8.2 g) as described inExample 7, 7.8 g (yield: 60%) are obtained; m.p. 58°-61° C. andelemental analysis correct.

IR Spectrum (KBr), cm⁻¹ : 3400, 3240, 3000-2780, 1675, 1595, 1585, 1530,1455, 1380, 1325, 1250, 1160, 1115, 750.

EXAMPLE 30 2-(2-Piperidinethoxy)ethyl2-(7-chloro-4-quinolyl)aminobenzoate ##STR54##

(A) 2-(2-Piperidinethoxy)ethyl antranilate (V, n=1, m=4):

8.2 g of 2-(2-piperidinethoxy)ethanol are reacted with 10.3 g of isatoicanhydride in 120 ml of toluene. 8.22 g (yield: 60%) of a yellow oil areisolated according to Example 22. Then, it is purified by carefuldistillation in ball furnace at 190°-210° C./10⁻³ Torr, as a viscousyellow oil with n_(D) ²⁰ =1.5528 and elemental analysis of C, H, Ncorrect.

IR Spectrum (KBr), cm⁻¹ : 3460, 3360, 3000-2700, 1685, 1615, 1290, 1240,1155, 1100, 750.

(B) Reaction of 4,7-dichloroquinoleine (VI, R=Cl):

By treating 2-(2-piperidinethoxy)ethyl antranilate (5.85 g) as describedabove, and 4,7-dichloroquinoleine (5.07 g), it is obtained a solid(yield: 57%) as described in Example 28; m.p. 75°-79° C. and elementalanalysis correct.

IR Spectrum (KBr), cm⁻¹ : 3440, 3240, 3300-2660, 1675, 1600, 1580, 1530,1450, 1375, 1255, 1130, 1085, 950, 745.

EXAMPLE 31 2-(2-Piperidinethoxy)ethyl2-(7-trifluoromethyl-4-quinolyl)aminobenzoate ##STR55##

By treating 2-(2-piperidinethoxy)ethyl antranilate (6.12 g) as describedin Example 30 and 4-chloro-7-trifluoromethylquinoleine (5.92 g) asdescribed in above examples, it is obtained a solid (yield: 53%); m.p.81°-83° C. and elemental analysis correct.

IR Spectrum (KBr), cm⁻¹ : 3290, 3000-2700, 1675, 1610, 1580, 1530, 1455,1250, 1150, 745.

EXAMPLE 32 2-(2-Homopiperidinethoxy)ethyl2-(7-chloro-4-quinolyl)aminobenzoate ##STR56##

(A) 2-(2-Homopiperidinethoxy)ethyl antranilate (V, n=1, m=6):

5.64 g of isatoic anhydride are reacted with 5.02 g of2-(2-homopiperidinethoxy)ethanol in 100 ml of toluene. 6.96 g (yield:85%) of a yellow oil are isolated according to Example 22; n_(D) ²⁰=1.5505, analysis elemental of C, H, N correct.

IR Spectrum (film), cm⁻¹ : 3450, 3360, 3000-2660, 1680, 1610, 1580,1480, 1290, 1240, 1150, 1110, 745.

(B) Reaction of 4,7-dichloroquinoleine (VI, R=Cl):

By treating 2-(2-homopiperidinethoxy)ethyl antranilate (6.12 g) asdescribed above, and 4,7-dichloroquinoleine (5.07 g) as described inExample 28, it is obtained a solid (yield: 51%); m.p. 62°-64° C. andelemental analysis correct.

IR Spectrum (KBr), cm⁻¹ : 3240, 3000-2700, 1675, 1600, 1570, 1520, 1445,1245, 1080, 875, 740.

EXAMPLE 33 2-(2-Homopiperidinethoxy)ethyl2-(7-trifluoromethyl-4-quinolyl)aminobenzoate (I, R=CF₃, n=1, m=6)

By treating 2-(2-homopiperidinethoxy)ethyl antranilate (6.12 g) asdescribed in Example 32, and 4-chloro-7-trifluoromethylquinoleine (5.92g) as described in above examples, 4.51 g (yield: 45%) are obtained;m.p. 53°-56° C. and elemental analysis correct.

IR Spectrum (KBr), cm⁻¹ : 3260, 3000-2700, 1670, 1595, 1580, 1520, 1445,1375, 1315, 1240, 1155, 1105, 740.

Without further analysis, the foregoing will so fully reveal the gist ofthe present invention that others can, by applying current knowledge,readily adapt it for various applications without omitting featuresthat, from the standpoint of prior art, fairly constitute essentialcharacteristics of the generic or specific aspects of this invention.

What is claimed as new and desired to be protected by Letters Patent isset forth in the appended claims: 1.2-Pyrrolidinylethyl-2-(7-trifluoromethyl-4-quinolyl-aminobenzoate or apharmacologically acceptacle acid addition salt thereof.
 2. Apharmaceutical composition having analgesic, antipyretic andanti-inflammatory activities which comprises a therapeutically effectiveamount of a compound according to claim 1 and a pharmaceuticallyacceptable carrier thereof.